This article is part of the Emerging Leaders in Pharmacology and Translational Science special issue. We are pleased to present this Special Issue of ACS Pharmacology and Translational Science showcasing emerging leaders. In putting together this Special Issue, our goal was 2-fold: (1) to highlight research that revealed new biological insights and/or challenged existing paradigms for drug action and therapeutic intervention, and (2) showcase research scientists early in their career stage who are emerging leaders in their fields of endeavor. Diverse therapeutic indications are covered within the issue, including Alzheimer’s diseases, cancer, chronic respiratory disorders, cardiometabolic diseases, and associated complications. In keeping with the spirit of our stated objectives, as the Guest Editors of this Special Issue, we are particularly delighted to bring you this special issue driven by the combination of an established scientist, Prof. Rebecca Ritchie, and an early mid-career scientist, Dr. Karen Gregory (whose brief biography is included below). The review by Donovan and Hansbro(1) discusses preclinical and clinical evidence for the role of interleukin (IL)-33, an inflammatory cytokine, in asthma and chronic obstructive pulmonary disease. The authors highlight key knowledge gaps in IL-33 biology, but also known differences in IL-33 biology between cell types and chronic respiratory conditions and how understanding these differences is critical to realize the therapeutic potential in targeting IL-33. Mutations in the cystic fibrosis transmembrane conductance regulator channel (CFTR) underscore the pathology of cystic fibrosis. In their review article, Ghelani and Schneider-Futschik(2) comprehensively review discovery, pharmacology and clinical development of CFTR modulators for cystic fibrosis. Importantly, the authors highlight the different mechanisms of action for modulating CFTR function and how emerging therapeutic agents may be used in combination with current therapies, or may have potential for other respiratory disorders. The neurodegenerative disorder Alzheimer’s disease (AD) is a major cause of dementia; recent high-profile phase III clinical trial failures have generated considerable interest in exploring novel therapeutic avenues. The contribution from Bagchi’s team, Riching et al.,(3) provides an overview of AD clinical trials to date and reviews the links between cardiometabolic disease and AD, presenting evidence for new therapeutic targets outside of the brain. Many of the debilitating complications of diabetes have fibrosis as a common feature in the affected organs, particularly in the heart and kidney. In their review, Perera and colleagues (led by Tate)(4) describe the intriguing bone morphogenetic protein (BMP) family, which forms a subgroup of the transforming growth factor-β (TGFβ) superfamily of over 30 members. Although TGFβ is commonly regarded as a pro-fibrotic signal, several BMP family members functionally oppose these pro-fibrotic actions, and may thus represent novel therapeutic targets for disorders of fibrosis such as those resulting from diabetes. Following on a similar vein, inflammation is a key driver of fibrosis in many organs. With this in mind, two manuscripts focus on novel approaches targeting inflammation and fibrosis in chronic disease. First, Fu et al. (led by Qin)(5) reviewed the potential therapeutic promise offered by lipoxin-A4 (and its derivatives). This class of endogenously generated mediators (and four generations of newer synthetic analogues with progressively increasing potency) promote the resolution of inflammation via the GPCR formyl peptide receptor-2 (FPR2), facilitating the healing process and restoration of tissue homeostasis in a range of settings of inflammation. The study reported by Wang et al.(6) describes the protective actions observed in response to the novel antifibrotic agent, relaxin, as well as to an angiotensin AT2 receptor agonist, alone and in combination, in a high salt diet model of cardiac fibrosis. These actions were accompanied by the blunting of cardiac inflammation but were independent of the lowering of blood pressure. Two papers offer perspectives on pharmacological and translational challenges associated with novel anticancer therapies. Gad and Balenga(7) provide a comprehensive review of the biological roles and pharmacology of adhesion G protein-coupled receptor (aGPCRs) family members. The authors highlight the therapeutic potential of the different members, including 15 orphan aGPCRs, as novel anticancer agents. The manuscript brings together an in-depth evaluation of how changes in expression of, and/or mutations within, different aGPCRs are linked to the top five most common cancers. In their study, Stewart and Davis(8) present assessment of different models for mammary gland epithelial cell function; of relevance to discovery of new breast cancer agents. Using a genetically encoded calcium-indicator to measure calcium signaling, the authors demonstrate with elegant imaging that primary 2D cultures and 3D organoids have distinct physiological responses compared to immortalized cell lines. The ability to quantify pharmacological responses in these 3D mini organs, offers the prospect of improving translation through early assessment of these more biologically complex systems within drug discovery pipelines. With this focused collection of contributions led by high-caliber students and early career researchers (ECRs) we hope to help raise the international profiles of the research led by these individuals and enhance their careers. For all Articles and Reviews within, the corresponding authors are all current graduate students or ECRs up to 10 years post-Ph.D., and are first or senior author on their manuscripts. Biographies of the lead ECR authors to each Article/Review within this Special Issue are included below. We hope you will join us in celebrating their research efforts and be on the lookout for their next big discovery! Dr. Chantal Donovan is an NHMRC Early Career Postdoctoral Research Fellow in the Centre for Inflammation, Centenary Institute and University of Technology Sydney. Her research is focused on understanding mechanisms that drive the development and progression of chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap, to develop novel therapies for these diseases. Dr. Elena Schneider-Futschik is a specialist in cystic fibrosis. As a National Health and Medical Research Council (NHMRC) Early Career Fellow she leads the cystic fibrosis pharmacology research program across the Department of Pharmacology & Therapeutics at the University of Melbourne aiming to optimize currently available treatments. Dr. Schneider-Futschik has received awards and research support from both public and philanthropic organizations including the Thoracic Society of Australia and New Zealand (TSANZ) and the NHMRC. Her senior author manuscript also features Drishti P. Ghelani, a motivated Honors student in the Department of Pharmacology & Therapeutics at the University of Melbourne with a passion for medical research. Dr. Rushita A. Bagchi is a postdoctoral fellow at the University of Colorado Anschutz Medical Campus. She earned her Ph.D. in Physiology and Pathophysiology at the University of Manitoba, Canada. She is currently using state-of-the-art epigenetic tools to better understand the mechanisms underlying tissue remodeling and its implications in the pathogenesis of cardiometabolic disease. Her long-term goal is to become an independent academic scientist, focusing on multiorgan crosstalk in metabolic disease. She is actively involved in several mentorship, teaching, and leadership initiatives. A proud alumna of the prestigious Lindau Nobel Laureate Meetings, her senior author manuscript also features ECR/student coauthors. Andrew Riching is currently a Ph.D. candidate in the Pharmacology program at the University of Colorado Anschutz Medical Campus mentored by Dr. Kunhua Song. His research focuses on identifying and understanding epigenetic mechanisms that regulate cardiomyocyte differentiation. A postdoctoral fellow at the University of Colorado Anschutz Medical Campus, Dr. Jennifer L. Major earned her Ph.D. in Cellular and Molecular Medicine at the University of Ottawa (Canada) in 2017 for her work on E2F transcription factors in cardiac development and disease. Dr. Mitchel Tate, Research Officer at the Baker Heart and Diabetes Institute, Melbourne, studies the mechanisms underlying diabetes-induced heart failure, with a particular interest in the role of fibrosis and inflammation. Notable achievements include acceptance into the JDRF Future Research Leaders Program, as well as an invitation to present at the leading heart research meeting, CSANZ-ISHR2018. In addition to his research activities, Dr. Tate is committed to raising awareness of diabetes, a disease often dubbed “the silent killer”, and particularly the cardiovascular complications of diabetes. He is also an active member of the Baker Institute Early Career Scientist Committee. His senior author manuscript also features a recent Honors graduate, Miss Nimna Perera, from Monash University, Australia, as first author. Dr. Cheng Xue (Helena) Qin is a Heart Foundation of Australia Future Leader Fellow and Group Leader at Baker Heart & Diabetes Institute in Australia. She has combined expertise in rational drug design, medicinal chemistry and preclinical models for cardiovascular disease. Her current research focuses on a family of G protein-coupled receptors, called formyl peptide receptors, involved in the regulation and resolution of inflammation. In recognition of her scientific achievements, she has been awarded prestigious prizes, including the Cardiac Society of Australia and New Zealand Ralph Reader Prize (2016), British Pharmacology/ASCEPT Outstanding Young Investigator Award (2015), 40 under 40: most influential Asian-Australian award (2019), and JDRF Future Leader (2019). Her senior author manuscript also features a Master’s student, Miss Ting Fu, from the University of Melbourne, Australia, as first author. Dr. Nariman Balenga is an Assistant Professor in the Department of Surgery at the University of Maryland School of Medicine. During his Ph.D. and postdoctoral studies, Dr. Balenga (1) characterized GPR55 signaling and discovered its functional crosstalk with cannabinoid receptors in inflammatory cells, (2) revealed the impact of RGS proteins in asthma and endocrine diseases, and (3) identified a novel procontractile biomarker in severe asthma patients. He started up his laboratory at the University of Maryland School of Medicine in 2015. His team employs multidisciplinary translational approaches in model cells and organisms to characterize the signaling and function of understudied orphan adhesion GPCRs, including ADGRG2/GPR64, in health and disease. His senior author manuscript is coauthored with Abanoub Gad, a graduate student in molecular medicine at the University of Maryland School of Medicine. Abanoub received his M.Sc.-Pharmacology from Thomas Jefferson University and is interested in elucidating the molecular underpinnings of tumorigenesis with the hope to discover novel targets to treat cancer. Dr. Felicity Davis completed her Ph.D. in cancer cell biology at The University of Queensland (Australia) in 2012. After performing postdoctoral research in the fields of calcium signaling (National Institute of Environmental Health Sciences, USA) and stem cell biology (University of Cambridge, UK), Dr. Davis returned to Australia to form her own research group at Mater Research Institute-University of Queensland. Her team uses advanced imaging to explore roles for intracellular calcium signaling in mammary gland development and function. Dr Teneale Stewart obtained her Ph.D. in cancer biology and pharmacology in 2016 from The University of Queensland, Australia. She subsequently conducted postdoctoral studies at the University of Minnesota (USA) where she investigated the regulation of endogenous DNA mutagens in breast cancer cells. Dr Stewart’s current postdoctoral research seeks to better understand developmental processes in the mammary gland, with a particular focus on the role of calcium signaling pathways. Dr. Yan Wang completed her Biomedical Science Honors Degree at Monash University, Australia, supervised by Prof. Widdop. She worked in the same lab as a Research Assistant for 3 years before commencing her Ph.D. candidature supervised by Prof. Widdop and Assoc. Prof. Samuel. Her research has focused on novel treatments for fibrosis in heart and kidney where she has helped lead collaborative projects related to AT₂R pathophysiology. Her research has contributed to patents and commercial funding opportunities. Yan’s Ph.D. thesis was conferred in January 2020 and she is currently a postdoctoral fellow in the Department of Pharmacology, Monash University. Dr. Karen Gregory is an Australian Research Council Future Fellow. She completed her Ph.D. from Monash University (Australia) in 2009, which was followed by postdoctoral training at Vanderbilt University (USA) supported by three highly competitive fellowships. Dr. Gregory is an internationally recognized expert in analytical and molecular pharmacology of G protein-coupled receptors (GPCRs), focusing on promising therapeutic targets for neuropsychiatric and neurological disorders. Her research seeks to understand novel paradigms of allosteric drug action at GPCRs with the goal of using these insights to facilitate rational drug discovery. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. This article references 8 other publications. This article has not yet been cited by other publications. This article references 8 other publications.

中文翻译：

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药理学和转化科学特刊的新兴领袖

本文是 药理学和转化科学领域的新兴领导者特刊。我们很高兴介绍本期《ACS药理学与转化科学》展示新兴领导者。在撰写此期特刊时，我们的目标是2个方面：（1）突出研究以揭示新的生物学见解和/或挑战现有的药物作用和治疗干预范例，以及（2）在职业生涯初期向研究科学家展示他们是他们努力领域中的新兴领导者。问题涵盖了多种治疗适应症，包括阿尔茨海默氏病，癌症，慢性呼吸系统疾病，心脏代谢性疾病和相关并发症。秉承既定目标的精神，作为本期特刊的特约编辑，我们非常荣幸地为您带来本期特刊，由资深科学家丽贝卡·里奇（Rebecca Ritchie）教授和职业初期的科学家共同推动博士 卡伦·格里高利（Karen Gregory）（其简短的传记包含在下面）。Donovan和Hansbro（1）的综述讨论了炎性细胞因子白介素（IL）-33在哮喘和慢性阻塞性肺疾病中的作用的临床前和临床证据。作者强调了IL-33生物学中的关键知识空白，但也知道了细胞类型与慢性呼吸状况之间IL-33生物学的差异，以及了解这些差异对于实现靶向IL-33的治疗潜力至关重要。囊性纤维化跨膜电导调节剂通道（CFTR）中的突变强调了囊性纤维化的病理。在他们的综述文章中，Ghelani和Schneider-Futschik（2）全面综述了囊性纤维化CFTR调节剂的发现，药理作用和临床发展。重要的，作者强调了调节CFTR功能的不同作用机制，以及新兴治疗剂如何与当前疗法结合使用，或可能具有其他呼吸系统疾病的潜力。神经退行性疾病阿尔茨海默氏病（AD）是痴呆症的主要原因。最近备受瞩目的III期临床试验失败引起了人们对探索新型治疗途径的浓厚兴趣。Bagchi小组的Riching等人（3）的贡献概述了迄今为止的AD临床试验，并回顾了心脏代谢疾病和AD之间的联系，为脑外新的治疗靶点提供了证据。糖尿病使许多令人衰弱的并发症具有纤维化，这是受累器官特别是心脏和肾脏的共同特征。在他们的评论中 Perera及其同事（由Tate领导）（4）描述了有趣的骨形态发生蛋白（BMP）家族，该家族构成了30多个成员的转化生长因子β（TGFβ）超家族的一个亚组。尽管TGFβ通常被认为是促纤维化信号，但一些BMP家族成员在功能上反对这些促纤维化作用，因此可能代表了针对诸如糖尿病引起的纤维化疾病的新型治疗靶标。沿着类似的静脉，炎症是许多器官纤维化的关键驱动因素。考虑到这一点，有两份手稿着眼于针对慢性疾病中炎症和纤维化的新方法。首先，傅等人。（由Qin领导）（5）回顾了脂蛋白A4（及其衍生物）提供的潜在治疗前景。这类内源性产生的介体（和四代更新的合成类似物，其效力逐渐增强）通过GPCR甲酰肽受体2（FPR2）促进炎症消退，在各种环境中促进愈合过程和组织稳态的恢复炎症。Wang等人（6）报道的研究描述了在高盐饮食的心脏纤维化模型中，单独或联合使用针对新型抗纤维化剂松弛素以及血管紧张素AT2受体激动剂的保护作用。这些动作伴有心脏炎症的减弱，但与血压降低无关。两篇论文提供了与新型抗癌疗法相关的药理和转化挑战的观点。Gad和Balenga（7）对粘附G蛋白偶联受体（aGPCRs）家族成员的生物学作用和药理作用进行了全面综述。作者强调了不同成员（包括15个孤儿aGPCR）作为新型抗癌药的治疗潜力。该手稿汇集了对不同aGPCR的表达变化和/或突变如何与前五种最常见癌症相关联的深入评估。在他们的研究中，Stewart和Davis（8）提出了不同模型对乳腺上皮细胞功能的评估。与发现新的乳腺癌药物有关。使用遗传编码的钙指示剂来测量钙信号，这组作者以高雅的成像证明，与永生化细胞系相比，原始2D培养物和3D类器官具有独特的生理反应。量化这些3D微型器官中药理反应的能力，提供了通过对药物发现管道中这些生物学上更复杂的系统进行早期评估来改善翻译的前景。通过这些由高素质学生和早期职业研究人员（ECR）领导的重点研究成果集，我们希望有助于提高这些人领导的研究的国际知名度，并改善他们的职业生涯。对于其中的所有文章和评论，相应的作者均为博士学位后长达10年的当前研究生或ECR，并且是其手稿的第一作者或高级作者。以下包括本期特刊中每篇文章/评论的主要ECR作者简介。我们希望您能与我们一起庆祝他们的研究成果，并期待他们的下一个重大发现！尚塔尔·多诺万（Chantal Donovan）博士是NHMRC炎症中心，百年研究所和悉尼科技大学的博士后早期研究员。她的研究专注于理解驱动慢性炎症性肺疾病（包括慢性阻塞性肺疾病（COPD），哮喘和哮喘-COPD重叠）发展和进展的机制，以开发针对这些疾病的新疗法。Elena Schneider-Futschik博士是囊性纤维化的专家。作为国家卫生与医学研究委员会（NHMRC）的早期职业研究员，她领导着墨尔本大学药理学与治疗学系的囊性纤维化药理学研究计划，旨在优化当前可用的治疗方法。Schneider-Futschik博士获得了包括澳大利亚和新西兰胸科协会（TSANZ）和NHMRC在内的公共和慈善组织的奖项和研究支持。她的资深作者手稿还有Drishti P. Ghelani，他是墨尔本大学药理学和治疗学系的荣誉学生，对医学研究充满热情。Rushita A.Bagchi博士是科罗拉多大学安舒兹大学医学校区的博士后。她获得了博士学位。加拿大曼尼托巴大学生理学和病理生理学专业。她目前正在使用最新的表观遗传学工具来更好地了解组织重塑的机制及其在心脏代谢疾病发病机理中的意义。她的长期目标是成为一名独立的学术科学家，专注于代谢疾病中的多器官串扰。她积极参与多项指导，教学和领导力计划。她是著名的Lindau诺贝尔奖获得者会议的骄傲的校友，她的资深作者手稿还包括ECR /学生合著者。安德鲁·里奇（Andrew Riching）目前是一名博士学位。在宋昆华博士的指导下，科罗拉多大学安舒兹医科大学药理学课程的候选人。他的研究专注于识别和理解调节心肌细胞分化的表观遗传机制。珍妮弗·梅杰（Jennifer L. Major）博士是科罗拉多大学安舒兹大学医学校区的博士后。她于2017年在渥太华大学（加拿大）的细胞与分子医学专业获得博士学位，致力于研究心脏发育和疾病中的E2F转录因子。米切尔·泰特博士墨尔本贝克心脏与糖尿病研究所的研究人员研究了糖尿病引起的心力衰竭的机制，尤其对纤维化和炎症的作用感兴趣。令人瞩目的成就包括被JDRF未来研究领导者计划所接受，并被邀请出席领先的心脏研究会议CSANZ-ISHR2018。除研究活动外，泰特博士还致力于提高人们对糖尿病的认识，这种疾病通常被称为“沉默的杀手”，尤其是糖尿病的心血管并发症。他还是贝克学院早期职业科学家委员会的活跃成员。他的高级作者手稿还包括澳大利亚莫纳什大学（Monash University）荣誉学士毕业生Nimna Perera小姐作为第一作者。秦承学博士是澳大利亚心脏基金会的未来领袖研究员，也是澳大利亚贝克心脏与糖尿病研究所的小组负责人。她在心血管疾病的合理药物设计，药物化学和临床前模型方面拥有丰富的专业知识。她目前的研究集中在G蛋白偶联受体家族（称为甲酰肽受体），涉及炎症的调节和消退。为表彰她的科学成就，她获得了许多著名的奖项，包括澳大利亚心脏病学会和新西兰拉尔夫读者奖（2016），英国药理学/ ASCEPT杰出青年研究者奖（2015），40岁以下40岁以下：最具影响力的亚洲人-澳大利亚大奖（2019）和JDRF未来领袖（2019）。她的高级作者手稿还包括硕士生傅婷小姐，来自澳大利亚墨尔本大学，第一作者。纳里曼·巴伦加（Nariman Balenga）博士是马里兰大学医学院外科系的助理教授。在他的博士学位期间 Balenga博士（1）对GPR55信号进行了表征，并发现了它与炎症细胞中大麻素受体的功能串扰；（2）揭示了RGS蛋白在哮喘和内分泌疾病中的作用；（3）鉴定了一种新的促收缩性生物标志物严重哮喘患者。他于2015年在马里兰大学医学院开始了他的实验室。他的团队在模型细胞和生物中采用了多学科的翻译方法，研究了在健康和疾病中被研究不足的孤儿粘附GPCR（包括ADGRG2 / GPR64）的信号传导和功能。他的资深作者手稿与Abanoub Gad合着，是马里兰大学医学院分子医学专业的研究生。Abanoub获得了托马斯·杰斐逊大学（Thomas Jefferson University）的医学理学硕士学位，并且对阐明肿瘤发生的分子基础感兴趣，希望能够发现治疗癌症的新靶标。费利西蒂·戴维斯博士完成了博士学位 2012年在昆士兰大学（澳大利亚）获得癌细胞生物学博士学位。在钙信号（美国国家环境健康科学研究所）和干细胞生物学（英国剑桥大学）领域进行博士后研究后，戴维斯博士回到澳大利亚，在昆士兰大学马特研究所（Mater Research Institute）成立了自己的研究小组。她的团队使用先进的成像技术来探索细胞内钙信号传导在乳腺发育和功能中的作用。特纳勒·斯图尔特博士获得博士学位 2016年获得澳大利亚昆士兰大学癌症生物学和药理学博士学位。随后，她在明尼苏达大学（美国）进行了博士后研究，在那里她研究了乳腺癌细胞中内源性DNA诱变剂的调控。斯图尔特博士目前的博士后研究旨在更好地了解乳腺的发育过程，特别着重于钙信号通路的作用。王彦博士在Widdop教授的指导下，在澳大利亚莫纳什大学（Monash University）完成了她的生物医学科学荣誉学位。在攻读博士学位之前，她曾在同一实验室担任研究助理3年。候选人由Widdop教授和Assoc监督。塞缪尔教授。她的研究专注于治疗心脏和肾脏纤维化的新疗法，并帮助领导了有关AT ₂ R病理生理学的合作项目。她的研究为专利和商业融资机会做出了贡献。严博士 该论文于2020年1月发表，目前是莫纳什大学药理学系的博士后。卡伦·格雷戈里（Karen Gregory）博士是澳大利亚研究委员会未来研究员。她完成了博士学位。2009年获得澳大利亚莫纳什大学（Monash University）的博士学位，随后在美国范德比尔特大学（Vanderbilt University）进行了博士后培训，并获得了三项竞争激烈的奖学金。Gregory博士是国际公认的G蛋白偶联受体（GPCR）的分析和分子药理学专家，致力于神经精神病学和神经疾病的有希望的治疗靶点。她的研究旨在了解GPCR上的变构药物作用的新颖范例，目的是利用这些见解来促进合理的药物发现。本社论中表达的观点只是作者的观点，不一定是ACS的观点。本文引用了其他8个出版物。本文尚未被其他出版物引用。